Systemic antibiotic treatment is often unsatisfactory in cases of osteomyelitis as well as infections in devitalized tissue, avascular scar tissue, and other areas with insufficient blood supply. Increasing blood levels of antibiotics can result in toxicity. For example, aminoglycosides can produce ototoxicity and nephrotoxicity. Another problem with long-term systemic treatment with antibiotics is the selection of drug-resistant mutants. In poorly vascularized areas, the infectious organism may encounter concentrations below the minimum lethal concentration which provides the opportunity for selection of a resistant form. Also in large-animal veterinary practice, the cost of the antibiotic for systemic use can be an issue.
Antibiotic formulations of polymethylmethacrylate have been employed as antiseptic bone cement and as beads either free or attached to a wire which is used for percutaneous removal [H. W. Bucholz. et al, Chiburg. 43, 446 (1970)]. PMMA is not bio-erodible.
An alternative is plaster of Paris (POP) which has been used without matrix biopolymers or medicinal complexing agents as CaSO41/2H2O [D. Mackey, et al, Clin. Orthop. 167, 263 (1982); and G. W. Bowyer, et al, J. Trauma, 36, 331 (1994)]. Polymethylmethacrylate and POP have been compared with regard to release profiles. Release rates from POP tend to be very fast.
Both polymethylmethacrylate and POP can be used to produce dimensionally stable beads and other structures. The acrylate cements or beads are formed by mixing pre-formed polymethylmethacrylate polymer, methylmethacrylate monomer, and a free-radical initiator. An exothermic reaction ensues which results in matrix temperatures as high as 100° C. Many antibiotics such as polymyxin and tetracycline are inactivated by these conditions [G. J. Popham, et al, Orth. Rev., 20, 331 (1991)]. As mentioned above, polymethylmethacrylate is biocompatible but not resorbable. Therefore, beads used to treat local infection must be retrieved by surgery which is accompanied by the risk of reinfection.
POP beads or pellets are resorbable but show inferior drug release profiles [G. W. Bowyer, et al, J. Trauma, 36, 331 (1994)].
Compositions containing hyaluronic acid have been used for topical administration of pharmacological substances [F. Della Valle, et al, U.S. Pat. Nos. 5,166,331 and 4,736,024].